WO2022057164A1

WO2022057164A1 - Preparation method for multi-target anti-tumor drug

Info

Publication number: WO2022057164A1
Application number: PCT/CN2021/070076
Authority: WO
Inventors: 胡双华; 张世喜; 郑琴香; 林寨伟
Original assignee: 广州南鑫药业有限公司
Priority date: 2020-09-21
Filing date: 2021-01-04
Publication date: 2022-03-24
Also published as: CN112159351A; CN112159351B

Abstract

Disclosed is a preparation method for a multi-target anti-tumor drug, which comprises the following steps: step 1: under the protection of nitrogen, using a Williamson ether synthesis method, 4-amino-3-fluorophenol and 4-chloro-2-picolinamide as raw materials, dimethyl sulfoxide and tetrahydrofuran as a mixed solvent, under the action of potassium tert-butoxide, conducting a reaction to generate 2-carbamoyl-4-((3-fluoro-4-amino)phenoxy)pyridine; and step 2: reacting the 2-carbamoyl-4-((3-fluoro-4-amino)phenoxy)pyridine with 4-chloro-3-(trifluoromethyl)phenyl isocyanate in a dioxane solvent to obtain a crude product, and performing purification to give a final product 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-formamide.

Description

A kind of preparation method of multi-target antitumor drug

technical field

The invention relates to the field of drug synthesis, in particular to a multi-target antitumor drug 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine -The preparation method of 2-carboxamide.

Background technique

Vascular endothelial growth factor (VEGF) is one of the most important cell growth factors in tumor angiogenesis. Tumor blood vessels are highly sensitive to VEGF, and the VEGF mRNA concentration is significantly higher in many tumor cells, including lung cancer. In addition, the Raf/MEK/ERK transduction pathway exists in all eukaryotic cells, and the specific cascade phosphorylation signals of Ras, Raf, MEK and ERK are transferred from the extracellular to the nucleus. Many tumor cells have up-regulation of this pathway. Once this pathway is over-activated, the acceleration of cell proliferation and the prolongation of cell survival will lead to the formation and development of tumors. 4-{4-[3-(4-Chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-carboxamide, the structure is as follows:

English name: 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-picolinamide, CAS number: 1343498-72-5, is an effective VEGF and RAF The kinase inhibitor belongs to a multi-targeted antitumor drug.

There is a preparation method of 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-carboxamide in the prior art, patent CN102643229A The reported method, 4-chloropyridine-2-carboxamide and 3-fluoro-4-aminophenol were dissolved in DMF, then t-BuOK was added, and 2-carbamoyl-4-(( 3-Fluoro-4-amino)phenoxy)pyridine. Then 2-carbamoyl-4-((3-fluoro-4-amino)phenoxy)pyridine was dissolved in ethyl acetate, then 3-trifluoromethyl-4-chlorophenylisocyanate was added, and stirred at 60°C After 4 hours, the solvent was evaporated under reduced pressure and purified by silica gel column to obtain 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2 as a white solid. - Formamide. The reaction conditions are harsh, involving high temperature and strong alkali reaction, and especially the reaction solvent DMF is partially degraded under these conditions, which is difficult to recover and apply mechanically, resulting in environmental protection pressure. At the same time, the yield is low, requiring silica gel column purification, which is not suitable for large-scale production.

Patent CN102885814A discloses the synthesis method of anticancer active compound 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-carboxamide, Using raw material 4-chloropyridine-2-carboxamide as raw material, 4-{4-[3-(4-chloro-3-trifluoromethylbenzene was prepared through two synthesis steps of metal-catalyzed coupling reaction and isocyanate addition reaction urea]-3-fluorophenoxy}pyridine-2-carboxamide. The reaction requires a metal composite catalyst, the cost is high, and the generated product has many impurities, the yield is not high, and does not meet the requirements of drug quality.

Therefore, in order to meet the requirements in production, the present application provides a new process, which is greatly improved in terms of industrial applicability, purity and yield.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a kind of industrialized preparation method for preparing compound 1, and the synthetic route it adopts is as follows:

The present invention includes a method for preparing compound 1:

The method is divided into two steps, including: the first step, nitrogen protection, using williamson ether synthesis method to synthesize intermediate 4: using compound 3 and compound 2 as raw materials, using dimethyl sulfoxide and tetrahydrofuran as mixed solvents, in tertiary Under the action of potassium butoxide, the reaction generates intermediate 4; in the second step, use isocyanate to form urea reaction to synthesize compound 1: react intermediate 4 and compound 5 in a dioxane solvent to obtain a crude product, and obtain compound 1 after purification .

Wherein, the molar ratio of dimethyl sulfoxide and tetrahydrofuran in the mixed solvent of the first step is 2-4:1, preferably the molar ratio is 2.5:1.

Wherein, in the first step, the mol ratio of the mixed solvent of dimethyl sulfoxide and tetrahydrofuran to potassium tert-butoxide is 5-15:1, preferably 10:1.

Wherein, the molar ratio of dioxane and intermediate 4 in the second step is 20-100:1, preferably the molar ratio is 50:1.

Wherein, the reaction temperature of the first step is 70-100°C, preferably the reaction temperature is 80-90°C.

Wherein, the reaction temperature of the second step is 45-65°C, preferably the reaction temperature is 50-60°C.

Wherein, the reaction time of the first step is 1.5-2 hours.

Wherein, the reaction time of the second step is 2-4 hours.

The specific preparation method is as follows:

Step 1: Add dimethyl sulfoxide and tetrahydrofuran into the reaction kettle, introduce nitrogen protection, then add potassium tert-butoxide, and after complete dissolution, control the temperature to 10-20°C. Continue to add 4-amino-3-fluorophenol, stir at room temperature for 10 minutes, add 4-chloro-2-pyridinecarboxamide, continue to stir for 10 minutes, and raise the temperature of the reaction solution to above 80°C within 30 minutes. Timing was started when the internal temperature rose to 80°C, and the reaction was kept at 85±2°C for 2.0 hours. After the reaction was completed, the temperature was cooled to below 20°C, 1M sodium hydroxide aqueous solution was added dropwise, and the temperature in the reactor was slowly lowered to 0-2°C after the drop was completed. The slurry was filtered while cold, and the filter cake was washed with deionized water. The filter cake was suspended in deionized water, beaten for 30 minutes, and filtered. The filter cake was washed with deionized water and dried under reduced pressure to obtain intermediate 4.

Step 2: add dioxane to the reaction kettle, protect with nitrogen, then add intermediate 4, stir, and heat up to 55°C. After the intermediate 4 was completely dissolved, 4-chloro-3-(trifluoromethyl) benzene isocyanate was dissolved in dioxane and pre-cooled to 10 ° C, and added dropwise to the reaction kettle for 1 hour. Body 4 continued to react for 1 hour. After cooling, the reaction solution was crystallized at 24°C for 15 hours to obtain compound 1.

Crystallization and purification of compound 1: centrifugal filtration, the filter cake was rinsed twice with ethyl acetate, and dried under reduced pressure to obtain a filter cake; methanol was poured into the reaction kettle, the above-mentioned compound 1 was added, the temperature was raised to reflux, the temperature was maintained for 3.0 hours, and then cooled, The inner temperature was lowered to 34°C for recrystallization; the crystals were rinsed twice with methanol and dried in vacuum for 72 hours to obtain off-white crystals.

For the first step ether-forming reaction of the technical solution of the present invention, patent US2005245530 reports a method for preparing compounds by microwave reaction in N-methylpyrrolidone, using diisopropylethylamine as a base. The rate is low and cannot be scaled up, not suitable for process development:

Regarding the second step of the urea-forming reaction in the technical solution of the present invention, patent WO2009111061 reports another route for synthesizing sorafenib by first preparing active compound 9 from compound 7, and then reacting with compound 6. However, experiments have shown that the yield of this route is low, and the reaction will become more complicated:

After groping and trial and error, the present invention finally finds out an industrialized method for preparing compound 1.

Compared with the prior art, the beneficial technical effects of the present invention are embodied in:

1) Compared with the prior art, the technical solution of the present invention improves the reaction yield by improving the solvent, and uses a specific tetrahydrofuran and dimethyl sulfoxide mixed solvent as a solvent, which greatly reduces the reaction temperature, improves the yield, and reduces simultaneously. production cost.

2) compared with the prior art, the technical solution of the present invention not only improves the product yield and purity, but also reduces the quantity and content of impurities by improving the reaction conditions, meets the requirements of the pharmaceutical industry, and avoids the use of chromatographic column purification, Therefore, the technical solution of the present invention is directly changed from the laboratory-level standard in the prior art to the industrial-level standard.

3) Compared with the prior art, the present application uses dioxane as the solution, avoiding the use of organic base reagents and the more toxic methylene chloride as a solvent and reducing the risk of environmental pollution.

4) Compared with the prior art, the present invention does not need to use metal catalysts, reduces the risk of heavy metal pollution, reduces costs, and avoids using relatively high toxicity toluene as a reaction solvent.

detailed description

Example 1 Preparation of 2-carbamoyl-4-((3-fluoro-4-amino)phenoxy)pyridine (compound 4)

19.36kg of dimethyl sulfoxide and 7.2kg of tetrahydrofuran were added to the 100L reaction kettle, nitrogen protection was introduced, 4.88kg of potassium tert-butoxide was added, and after it was completely dissolved, the temperature was controlled to 10-20°C. Continue to add 4.54kg of 4-amino-3-fluorophenol (compound 3), stir at room temperature for 10 minutes, add 5.57kg of 4-chloro-2-pyridinecarboxamide (compound 2), continue to stir for 10 minutes, and react within 30 minutes The liquid temperature rose to above 80°C. Timing was started when the internal temperature rose to 80°C, and the reaction was kept at 85±2°C for 2.0 hours. After the reaction was completed, the temperature was cooled to below 20°C, 70 kg of 1M sodium hydroxide aqueous solution was added dropwise, and the temperature in the reactor was slowly lowered to 0 to 2°C after the completion of the dropping. The slurry was filtered while cold, and the filter cake was washed with 120 kg of deionized water. The filter cake was suspended in 80 kg of deionized water, beaten for 30 minutes, and filtered. The filter cake was washed with 20 kg of deionized water, and dried under reduced pressure to obtain Intermediate 4, which was weighed to 6.5 kg (the yield was about 82.3%).

Example 2 Preparation of 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-carboxamide (Compound 1)

37.3kg of dioxane was added to the 100L reaction kettle, nitrogen was protected, and 2.5kg of intermediate 4 was added, stirred, and heated to 55°C. After the intermediate 4 was completely dissolved, 2.2 kg of 4-chloro-3-(trifluoromethyl) benzene isocyanate (compound 5) was dissolved in 6.7 kg of dioxane and pre-cooled to 10 ° C, and added dropwise to 100 L for 1 hour In the reaction kettle, continue to react with Intermediate 4 for 1 hour after dropping. After cooling, the reaction solution was crystallized at 24°C for 15 hours to obtain compound 1. Centrifugal filtration, the filter cake was rinsed twice with 6.0kg of ethyl acetate, and the weight of the filter cake was 3.8kg after drying under reduced pressure. 40.0 kg of methanol was poured into a 100L reaction kettle, the above-mentioned compound 1 was added, the temperature was raised to reflux, the temperature was maintained for 3.0 hours, and the temperature was lowered to 34° C. for recrystallization. The crystals were rinsed twice with 4.0 kg of methanol, and dried in vacuum for 72 hours to obtain 3.5 kg of off-white crystals, the yield was about 75%, and the HPLC purity: ≥99.5%. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 7.17(d,1H), 7.21(m,1H), 7.32(m,1H), 7.41(d,1H), 7.62(d,2H), 7.73 (s, 1H), 8.17 (m, 3H), 8.54 (d, 1H), 8.72 (s, 1H), 9.51 (s, 1H); MS (ESI) m/z: 469.1 (M+H) ⁺ .

Example 3 Preparation of 2-carbamoyl-4-((3-fluoro-4-amino)phenoxy)pyridine (compound 4)

23.23kg of dimethyl sulfoxide and 6.0kg of tetrahydrofuran were added to the 100L reactor, nitrogen protection was introduced, 5.37kg of potassium tert-butoxide was added, and after it was completely dissolved, the temperature was controlled to 10-20°C. Continue to add 4.99kg of 4-amino-3-fluorophenol (compound 3), stir at room temperature for 10 minutes, add 6.13kg of 4-chloro-2-pyridinecarboxamide (compound 2), continue to stir for 10 minutes, and react within 30 minutes The liquid temperature rose to above 80°C. Timing was started when the internal temperature rose to 80°C, and the reaction was kept at 85±2°C for 2.0 hours. After the reaction was completed, the temperature was cooled to below 20° C., 80 kg of 1M sodium hydroxide aqueous solution was added dropwise, and the temperature in the reaction kettle was slowly lowered to 0 to 2° C. after the completion of the dropping. The slurry was filtered while cold, and the filter cake was washed with 140 kg of deionized water. The filter cake was suspended in 90 kg of deionized water, beaten for 30 minutes, and filtered. The filter cake was washed with 25 kg of deionized water, and dried under reduced pressure to obtain Intermediate 4, which weighed 6.9 kg (yield was about 81.4%).

Example 4 Preparation of 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-carboxamide (Compound 1)

41.0kg of dioxane was added to the 100L reaction kettle, nitrogen was protected, 3.0kg of intermediate 4 was added, stirred, and heated to 60°C. After the intermediate 4 was completely dissolved, 2.6kg of 4-chloro-3-(trifluoromethyl)benzene isocyanate (compound 5) was dissolved in 7.4kg of dioxane and pre-cooled to 10°C, and added dropwise to 100L in 1 hour In the reaction kettle, continue to react with Intermediate 4 for 1 hour after dropping. After cooling, the reaction solution was crystallized at 25°C for 12 hours to obtain compound 1. Centrifugal filtration, the filter cake was rinsed twice with 7.0kg of ethyl acetate, and the weight of the filter cake was 4.4kg after drying under reduced pressure. Into a 100L reaction kettle, 45.0 kg of methanol was poured, the above-mentioned compound 1 was added, the temperature was raised to reflux, the temperature was maintained for 3.0 hours, and the temperature was lowered to 32° C. for recrystallization. The crystals were rinsed twice with 4.5 kg of methanol, and dried in vacuum for 72 hours to obtain 3.9 kg of off-white crystals with a yield of about 70% and HPLC purity: ≥99.4%.

Example 5 Preparation of 2-carbamoyl-4-((3-fluoro-4-amino)phenoxy)pyridine (compound 4)

12.90kg of dimethyl sulfoxide and 4.3kg of tetrahydrofuran were added to the 100L reaction kettle, nitrogen protection was introduced, 4.0kg of potassium tert-butoxide was added, and after it was completely dissolved, the temperature was controlled to 10-20°C. Continue to add 3.78kg of 4-amino-3-fluorophenol (compound 3), stir at room temperature for 15 minutes, add 4.64kg of 4-chloro-2-pyridinecarboxamide (compound 2), continue to stir for 15 minutes, and react within 40 minutes The liquid temperature rose to above 80°C. Start timing when the internal temperature rises to 80°C, and keep the reaction at 80±2°C for 2.5 hours. After the reaction was completed, the temperature was cooled to below 20°C, 50 kg of 1M sodium hydroxide aqueous solution was added dropwise, and the temperature in the reaction kettle was slowly lowered to 0 to 2°C after the completion of the dropping. The slurry was filtered while cold, and the filter cake was washed with 100 kg of deionized water. The filter cake was suspended in 60 kg of deionized water, beaten for 30 minutes, and filtered. The filter cake was washed with 15 kg of deionized water, and dried under reduced pressure to obtain Intermediate 4, which weighed 5.2 kg (the yield was about 78.4%).

Example 6 Preparation of 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-carboxamide (Compound 1)

25.0kg of dioxane was added to the 100L reaction kettle, nitrogen was protected, 1.7kg of intermediate 4 was added, stirred, and heated to 50°C. After the intermediate 4 was completely dissolved, 1.5 kg of 4-chloro-3-(trifluoromethyl) benzene isocyanate (compound 5) was dissolved in 4.5 kg of dioxane and pre-cooled to 10 ° C, and added dropwise to 100 L for 1 hour In the reaction kettle, continue to react with Intermediate 4 for 1 hour after dropping. After cooling, the reaction solution was crystallized at 24°C for 15 hours to obtain compound 1. Centrifugal filtration, the filter cake was rinsed twice with 5.0kg of ethyl acetate, and the weight of the filter cake was 2.4kg after drying under reduced pressure. 30.0kg of methanol was injected into a 100L reaction kettle, the above-mentioned compound 1 was added, the temperature was raised to reflux, the temperature was maintained for 3.0 hours, cooled, and the internal temperature was lowered to 32° C. for recrystallization. The crystals were rinsed twice with 3.0 kg of methanol, and dried in vacuum for 72 hours to obtain 2.2 kg of off-white crystals with a yield of about 71% and HPLC purity: ≥99.3%.

Embodiment 7 Compound 1 quality standard and detection method

Purity determination method: (HPLC, area normalization method.)

Chromatographic column: Waters Symmetry C18 4.6×50mm, 3.5um Detector: UV detector;

Flow rate: 1.0mL/min;

Detection wavelength 262nm;

Concentration 0.3mg/mL;

The injection volume is 10μl;

Diluent: acetonitrile/methanol=1/1(v/v);

Mobile phase A: 10mmol/L ammonium formate;

Mobile phase B: acetonitrile/methanol=1/1 (v/v);

The measurement results:

The compound 1 obtained in Example 2 was measured, and the results were as follows:

Among them, the impurities are as follows:

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection of the present invention. within the range.

Claims

A preparation method of multi-target antitumor drug compound 1, is characterized in that comprising the steps:

The first step, use williamson ether synthesis method to synthesize intermediate 4: take compound 3 and compound 2 as raw materials, take tetrahydrofuran and dimethyl sulfoxide as mixed solvent, under the effect of potassium tert-butoxide, the reaction generates intermediate 4;

In the second step, use isocyanate to form urea reaction to synthesize compound 1: react with intermediate 4 and compound 5 in dioxane solvent to obtain a crude product, and after refining, obtain compound 1;

The specific chemical reaction formula is as follows:
According to the preparation method of claim 1, it is characterized in that the mol ratio of dimethyl sulfoxide and tetrahydrofuran in the mixed solvent of the first step is 2-4:1, and the preferred mol ratio is 2.5:1.
According to the preparation method of claim 1, it is characterized in that in the first step, the mixed solvent of dimethyl sulfoxide and tetrahydrofuran and the potassium tert-butoxide mol ratio are 5-15:1, preferably mol ratio 10:1.
The preparation method according to claim 1, wherein the mol ratio of dioxane and intermediate 4 in the second step is 20-100:1, preferably 50:1.
The preparation method according to claim 1 is characterized in that the reaction temperature of the first step is 70-100°C, preferably the reaction temperature is 80-90°C.
The preparation method according to claim 1 is characterized in that the reaction temperature of the second step is 45-65°C, preferably the reaction temperature is 50-60°C.
The preparation method according to claim 1 is characterized in that the reaction time of the first step is 1.5-2 hours.
The preparation method according to claim 1 is characterized in that the reaction time of the second step is 2-4 hours.
A method for preparing a multi-target antitumor drug compound 1, comprising the following steps:

Step 1: Add dimethyl sulfoxide and tetrahydrofuran into the reaction kettle, introduce nitrogen protection, then add potassium tert-butoxide, and after complete dissolution, control the temperature to 10-20°C. Continue to add 4-amino-3-fluorophenol, stir at room temperature for 10 minutes, add 4-chloro-2-pyridinecarboxamide, continue to stir for 10 minutes, and raise the temperature of the reaction solution to above 80°C within 30 minutes. Timing was started when the internal temperature rose to 80°C, and the reaction was kept at 85±2°C for 2.0 hours. After the reaction was completed, the temperature was cooled to below 20°C, 1M aqueous sodium hydroxide solution was added dropwise, and the temperature in the reaction kettle was slowly lowered to 0～2°C after the completion of the dropping. The slurry was filtered while cold, and the filter cake was washed with deionized water. The filter cake was suspended in deionized water, beaten for 30 minutes, and filtered. The filter cake is washed with deionized water and dried under reduced pressure to obtain Intermediate 4;

Step 2: add dioxane to the reaction kettle, protect with nitrogen, then add intermediate 4, stir, and heat up to 55°C. After the intermediate 4 was completely dissolved, 4-chloro-3-(trifluoromethyl) benzene isocyanate was dissolved in dioxane and pre-cooled to 10 ° C, and added dropwise to the reaction kettle for 1 hour. Body 4 continued to react for 1 hour. After cooling, the reaction solution was crystallized at 24°C for 15 hours to obtain compound 1;

Crystallization and purification of compound 1: centrifugal filtration, the filter cake was rinsed twice with ethyl acetate, and dried under reduced pressure to obtain a filter cake; methanol was poured into the reaction kettle, the above-mentioned compound 1 was added, the temperature was raised to reflux, the temperature was maintained for 3.0 hours, and then cooled, The internal temperature was lowered to 34°C for recrystallization; the crystallization was rinsed twice with methanol, and dried in vacuum for 72 hours to obtain off-white crystals;

The specific chemical reaction formula is as follows: